SBIR-STTR Award

?Multiple myeloma (MM) is the second most common hematological malignancy in the United States, and remains an incurable disease since nearly all MM patients will eventually relapse and develop resistance to currently available drugs. Sphingolipid metabolism is being increasingly recognized as a key pathway in tumor biology. In particular, sphingosine kinases (SK1 and SK2) provide a potential site for manipulation of the ceramide/ sphingosine 1-phosphate (S1P) rheostat that regulates the balance between tumor cell proliferation and apoptosis, as well as tumor sensitivity to drugs and radiation. We have recently demonstrated that SK2 is overexpressed in MM and that inhibition of SK2 in MM cell lines by ABC294640 down-regulates c-Myc expression and promotes apoptosis in MM cells. Importantly, ABC294640 also effectively inhibits tumor growth in vivo in myeloma xenograft models. ABC29460 has recently completed phase I testing in patients with advanced solid tumors, and we hypothesize that this drug will be useful for the treatment of MM patients. In this phase 2 SBIR project, we will conduct the following Specific Aims: 1: Perform a phase Ib clinical trial to determine the safety, pharmacokinetics and pharmacodynamics of ABC294640 when combined with dexamethasone in relapsed/refractory MM patients. We will perform a phase 1b trial with up to 18 patients to determine the safety, maximal tolerated dose (MTD), pharmacokinetics and pharmacodynamics of ABC294640 combined with dexamethasone in relapsed and/or refractory MM patients who have previously been treated with both a proteasome inhibitor and an immunomodulatory agent; and 2: Perform a phase II clinical trial to determine the preliminary efficacy of ABC294640 combined with dexamethasone in relapsed/refractory MM patients. Once the MTD has been established, up to 36 additional patients with refractory/relapsed MM will be enrolled at the MTD to confirm safety and to investigate preliminary efficacy in this population. We expect that this clinical trial will have important implications in the treatment of MM. We believe that the proposed studies constitute a focused approach for developing a novel treatment for patients with MM, a disease with a high unmet clinical need. If positive, these data will provide justification for a larger, multi- center phase III study.

Public Health Relevance Statement:


Public Health Relevance:
Multiple myeloma (MM) is a common but incurable disease that requires new therapies. Sphingolipid metabolism is being increasingly recognized as a key pathway in cancer biology, and is changed in MM cells. We have developed the first clinical drug that inhibits a key enzyme (SK2) and have extensive preclinical data that suggest it will be active against MM. This project will extend the clinical testing of this drug into MM patients to assess its safety and to provide a preliminary estimation of its therapeutic potential. Successful completion of these studies could have important implications for the treatment of MM.

NIH Spending Category:
Cancer; Clinical Research; Clinical Trials and Supportive Activities; Hematology; Orphan Drug; Rare Diseases

Project Terms:
absorption; Accounting; Apoptosis; c-myc Genes; Cancer Biology; Cell Line; Cell Proliferation; Cells; Ceramides; Cessation of life; Clinical; Clinical Trials; Data; Development; Dexamethasone; Disease; Dose; Drug Kinetics; Enrollment; Enzymes; Equilibrium; Goals; Hematologic Neoplasms; in vivo; inhibitor/antagonist; Kinetics; Maximum Tolerated Dose; Medical; Metabolism; Multiple Myeloma; neoplastic cell; novel; novel therapeutics; overexpression; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; phase 3 study; Phase II Clinical Trials; Plasma; Population; pre-clinical; Proteasome Inhibitor; public health relevance; Radiation; Refractory; Relapse; research clinical testing; Resistance development; RNA Interference; Safety; Site; Small Business Innovation Research Grant; Solid Neoplasm; Sphingolipids; sphingosine 1-phosphate; sphingosine kinase; Testing; Therapeutic; Therapeutic Agents; tumor; Tumor Biology; tumor growth; United States; Xenograft Model

Multiple myeloma (MM) is the second most common hematological malignancy in the United States, and remains an incurable disease since nearly all MM patients will eventually relapse and develop resistance to currently available drugs. Sphingolipid metabolism is being increasingly recognized as a key pathway in tumor biology. In particular, sphingosine kinases (SK1 and SK2) provide a potential site for manipulation of the ceramide/ sphingosine 1-phosphate (S1P) rheostat that regulates the balance between tumor cell proliferation and apoptosis, as well as tumor sensitivity to drugs and radiation. We have recently demonstrated that SK2 is overexpressed in MM and that inhibition of SK2 in MM cell lines by ABC294640 down-regulates c-Myc expression and promotes apoptosis in MM cells. Importantly, ABC294640 also effectively inhibits tumor growth in vivo in myeloma xenograft models. ABC29460 has recently completed phase I testing in patients with advanced solid tumors, and we hypothesize that this drug will be useful for the treatment of MM patients. In this phase 2 SBIR project, we will conduct the following Specific Aims: 1: Perform a phase Ib clinical trial to determine the safety, pharmacokinetics and pharmacodynamics of ABC294640 when combined with dexamethasone in relapsed/refractory MM patients. We will perform a phase 1b trial with up to 18 patients to determine the safety, maximal tolerated dose (MTD), pharmacokinetics and pharmacodynamics of ABC294640 combined with dexamethasone in relapsed and/or refractory MM patients who have previously been treated with both a proteasome inhibitor and an immunomodulatory agent; and 2: Perform a phase II clinical trial to determine the preliminary efficacy of ABC294640 combined with dexamethasone in relapsed/refractory MM patients. Once the MTD has been established, up to 36 additional patients with refractory/relapsed MM will be enrolled at the MTD to confirm safety and to investigate preliminary efficacy in this population. We expect that this clinical trial will have important implications in the treatment of MM. We believe that the proposed studies constitute a focused approach for developing a novel treatment for patients with MM, a disease with a high unmet clinical need. If positive, these data will provide justification for a larger, multi- center phase III study.

Public Health Relevance Statement:


Public Health Relevance:
Multiple myeloma (MM) is a common but incurable disease that requires new therapies. Sphingolipid metabolism is being increasingly recognized as a key pathway in cancer biology, and is changed in MM cells. We have developed the first clinical drug that inhibits a key enzyme (SK2) and have extensive preclinical data that suggest it will be active against MM. This project will extend the clinical testing of this drug into MM patients to assess its safety and to provide a preliminary estimation of its therapeutic potential. Successful completion of these studies could have important implications for the treatment of MM.

NIH Spending Category:
Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Hematology; Orphan Drug; Rare Diseases

Project Terms:
absorption; Accounting; Apoptosis; c-myc Genes; Cancer Biology; Cell Line; Cell Proliferation; Cells; Ceramides; Cessation of life; Clinical; Clinical Trials; Data; Development; Dexamethasone; Disease; Dose; Drug Kinetics; Enrollment; Enzymes; Equilibrium; Goals; Health; Hematologic Neoplasms; in vivo; inhibitor/antagonist; Kinetics; Maximum Tolerated Dose; Medical; Metabolism; Multiple Myeloma; neoplastic cell; novel; novel therapeutics; overexpression; Pathway interactions; Patients; Pharmaceutical Preparations; pharmacodynamic biomarker; Pharmacodynamics; Phase; phase 3 study; Phase II Clinical Trials; Plasma; Population; pre-clinical; Proteasome Inhibitor; Radiation; Refractory; Relapse; research clinical testing; Resistance development; RNA Interference; Safety; Site; Small Business Innovation Research Grant; Solid Neoplasm; Sphingolipids; sphingosine 1-phosphate; sphingosine kinase; Testing; Therapeutic; Therapeutic Agents; tumor; Tumor Biology; tumor growth; United States; Xenograft Model